I'd like to thank the organizers of this session and the Internal Medicine section for inviting me to present today in the Internal Medicine's Year in Review. So my half of the presentation is going to focus in on the biggest papers of the year focused on COVID-19 critical illness. And I title this, the Internal Medicine Year in Review, Another Year in COVID-19 as we've completed the second year of the pandemic. Now to give a brief outline, I'm going to focus on three aspects of new therapies for COVID-19 that are geared towards the host response to infection with SARS-CoV-2, namely steroids, anti-interleukin-6 therapies, and Janus kinase or JAK inhibitors. One conceptual way to think about treatment for COVID-19 is to think about what phase patients are in COVID-19 or what stage or severity that they are. And there's been a lot of focus on the early stages when viral replication is high and developing therapies to inhibit viral replication. And that's really the focus of outpatient therapies for COVID-19. Where it starts to get into our specialty is when patients progress into moderate and then severe and eventually critical illness. And it seems that in this phase of the syndrome COVID-19, inflammation and overactive inflammation really drives the organ injury rather than just viral replication. So the role of antivirals seems to be less so later on towards severe illness and critical illness. And that's where we get to targeting the host response to infection by decreasing inflammation. Now in the first year of the pandemic, in 2020, our treatments for severe COVID-19 were rather limited. They were mostly limited to supportive care, namely high flow nasal cannula oxygen, invasive mechanical ventilation, and then the highest standards of care with ARDS therapies, such as low stretch mechanical ventilation and prone positioning. Now in terms of therapeutics, we had pretty limited therapeutics. The first therapeutic to get emergency use authorization approval was remdesivir, an antiviral drug. Now this drug seemed to show some benefit, but really isn't a game changer for severe COVID-19 treatment. The first treatment to really show a significant benefit in mortality, however, was dexamethasone, which was published first in preprint in late 2020 and then published formally in 2021. I'll briefly review that trial in a few slides. Now in 2021, we've expanded our knowledge to actually have specific treatments that may benefit patients with COVID-19 and severe COVID-19 specifically. And those include treatments targeting the inflammation cascades of interleukin-6 activation and JAK kinase activation. So for the first part of the talk, I'm going to talk about steroids for severe COVID-19. Now I'm not going to spend too much time on this because it was partially covered last year, but I do want to review it because it's been such an important breakthrough in the last in 2021. So the largest study ever to look at steroids in hospitalized patients with COVID-19 is the recovery study. And this is a randomized controlled trial that was performed in the United Kingdom and it randomized patients to receive dexamethasone 6 milligrams daily for up to 10 days versus usual care. And they randomized 2,104 patients to receive dexamethasone and 4,321 patients to receive control. Now their outcome demonstrated a mortality benefit where the mortality in the dexamethasone group was 22.9% and 25.7% in the control group at 28 days. Now at that time, there was equipoise as to whether steroids would benefit patients with COVID-19. There was the potential benefit of reducing inflammation, but also the potential harm of allowing for further viral replication and the prior evidence that showed that in influenza steroids may be harmful. And you can see here in this mortality curve that very early the two curves separate showing a small benefit to dexamethasone in terms of mortality. And if you look at specifically the patients stratified by whether they required invasive mechanical ventilation, oxygen, or were not on oxygen at time of randomization, you'll see that the largest benefits were in patients with invasive mechanical ventilation, but there was also a statistically significant benefit in patients that received oxygen at enrollment. But those that were not on oxygen didn't seem to see a benefit from dexamethasone, although this group was rather small. And now in meta-analysis, looking at multiple different studies, all of which are smaller than the recovery study, but are significant, we now have a nice signal that dexamethasone or any steroid really shows a benefit in severe COVID-19. Now there's been several different doses of steroids used, several different kinds of steroids. High dose dexamethasone was suggested to be beneficial in ARDS, in the dexa-ARDS study, so that's been considered as a possibility, as well as hydrocortisone and methylprednisolone. Now the highest quality of evidence comes from the recovery study, which used a low dose of dexamethasone, which may be associated with lower risk of side effects from a steroid infusion. However, if dexamethasone is not available, other steroids seem to have a similar benefit. Now the questions that are still being asked are relevant to steroids. The most recent question that's been published is, what dose of steroids should we use? This was a trial published this year, looking at 12 milligrams versus 6 milligrams of dexamethasone, saying do we need more steroids or less steroids? This was a blinded, randomized controlled trial in Europe and India, the COVID Steroids 2 Trial Group. They included patients with COVID-19 confirmed, and that were on at least 10 liters per minute of oxygen, or who were mechanically ventilated. And they randomized to IV dexamethasone at 12 milligrams per day versus 6 milligrams per day. And their primary outcome were days alive without life support at 28 days. And in this study, they randomized 1,000 subjects. And they saw that in the higher group, the days alive without life support was about one and a half days higher than the 6 milligram per day group. And this just missed statistical significance. The mortality also seemed to trend towards a mortality benefit at 27.1% in the higher dose dexamethasone group versus 32.3% in the lower dose. However, again, this was not statistically significant. But if you look at the time curve to death here, you can see that there seems to be a benefit to 12 milligrams of dexamethasone, or a potential benefit that doesn't quite reach statistical significance. It leaves the question unanswered as to whether 6 milligrams or 12 milligrams are a benefit in different patient populations. Now it is important that this trial was done specifically to look at steroids and didn't include patients that received other immunomodulators that I'm going to talk about a little later in this talk. So that moves us to the next group of drugs that have developed for COVID-19. And those are the interleukin-6 antagonists in severe COVID-19. Interleukin-6 is a inflammatory cytokine that's released in response to infection and stimulates inflammatory pathways through the interleukin-6 receptor that can lead to sepsis. Tocilizumab and serolumab are monoclonal antibodies that inhibit both membrane-bound and soluble IL-6 receptors. They are used to treat inflammatory conditions such as rheumatoid arthritis and cytokine release syndrome after CAR-T therapy, CAR-T cell therapy. Now early in the pandemic, people were using tocilizumab without randomized controlled trial evidence to potentially treat the inflammatory storm that was being seen with COVID-19. But this year, we actually have several trials that are suggesting a benefit to the use of anti-IL-6 therapy. The first large study to demonstrate a benefit to IL-6 receptor antagonists was the REMAP-CAP study published in 2021. The REMAP-CAP study is very interesting because it's both innovative by identifying a new therapeutic for severe COVID-19, but also employs very innovative study design relying on an adaptive platform trial that employs Bayesian statistics. The trial really demonstrated how COVID-19 has accelerated research in critical care and moved us towards more innovative methods and efficient methods of identifying therapeutics. Now this was an international multifactorial adaptive platform trial. Patients were included if they were adults admitted to an ICU with COVID-19 and required respiratory or cardiovascular support. Now respiratory support was defined as invasive or non-invasive mechanical ventilation, including high flow nasal cannula as long as the FiO2 was greater than 40%. Cardiovascular support was defined as being on vasopressors or inotropes. Now despite having these two forms of organ support, the large majority of enrolled patients met the respiratory support requirement. And even if they met the cardiovascular support requirement, they also tended to meet the respiratory support requirement. Now they were enrolled within 24 hours after starting organ support. And for this part of the platform trial, now as a platform trial, this included testing multiple different therapies. But for the immune modulation therapy domain, they randomized patients to tocilizumab, sarilimab, or control. And they actually had several other arms aimed at other cytokines besides IL-6, but those arms tended to be small and weren't included in this publication. Now they randomized patients was randomized based on a randomized algorithm, but also on availability of the drugs at the particular center. And there were times where sarilimab was not available during the study. Now their primary outcome was number of respiratory and cardiovascular organ support free days up to day 21. And those days were defined the same way the inclusion criteria were defined in terms of respiratory and cardiovascular organ support. And death as a competing risk was assigned the extreme. So it was assigned minus one. Now their statistics are complicated and I can't fully explain them in this forum. But they used a Bayesian design with regular estimates of the posterior probability and stopping rules for efficacy and futility. So the Bayesian study design allows the study to continue with no maximum maximal sample size. So sample size is not calculated a priori, but the trial continues until it reaches one of the stopping criteria. So the study will continue to enroll until the preset specified posterior probabilities of efficacy or futility are met. The benefits to Bayesian approach include the ability to improve efficiency by stopping the trial once the probabilities are met, but also not running into the problem of incorrect sample sizes and underpowering. The problems include difficulty estimating costs up front and difficulties in interpreting among clinicians who are versed, well versed in the frequentist statistics, but may not fully understand Bayesian statistics. Now what they found in their primary outcome is that the median organ support free days in the tosalizumab arm was 10. The serolumab arm was 11, although this was a much smaller group, 48 patients versus 353. And then among the 402 controls, the median organ support free days was zero. And remember minus one means that the patient died. Now this was with an adjusted odds ratio for tosalizumab and serolumab compared to control were statistically significant benefits in organ free support days. And if you look at in-hospital mortality, the in-hospital mortality was 28% in tosalizumab, 22% in serolumab and 36% in control. Another statistically significant mortality benefit. Now this trial was published in the context of several other trials that are already been published that showed no benefit in mortality to use of IL-6 inhibitors like tosalizumab. But the authors argue there are several differences to this trial compared to the other trials that were previously published. The first is they had a much larger sample size than the prior studies who were likely all underpowered to identify a mortality benefit of IL-6 inhibition. This trial also only includes critically ill patients. Older trials tended to include patients when they first presented with COVID-19 and not just when they progressed to critical illness. And those patients might have actually watered down the effect of tosalizumab. The drug was also given very early in critical illness within the first 24 hours in this study. And most patients in this study also received steroids as opposed to prior studies that were done prior to the publication of the benefit of corticosteroids for COVID-19. Now on the other hand, there's one potential criticism of this study that might explain why there was a benefit identified that wasn't in older studies. And that was that it was open label. Prior studies were blinded and this study was not conducted in a blinded manner and therefore could have influences on the primary outcomes. Now another study that was even larger that confirmed the benefits, the potential benefits of tosalizumab in patients admitted to the hospital with COVID-19 was again the recovery study. And you'll remember this is the same study that identified a benefit of dexamethasone. After they finished dexamethasone, they moved on to looking at tosalizumab. So this was a randomized controlled open label platform trial that is now testing tosalizumab. It included patients that tested positive for COVID-19 who had some degree of hypoxia. And for the purposes of this part of the trial, they also had to have markers of inflammation, specifically the CRP greater than 75 milligrams per liter. Now they were enrolled once they met 21 days after the main enrollment. So patients could be enrolled in the main platform trial, testing multiple different therapies once they were admitted with COVID-19. And then they could be followed as long as 21 days for the development of hypoxia and an elevated CRP. If they develop that, they received a dose of tosalizumab. And then if they didn't improve within 12 to 24 hours, at the discretion of the treating clinicians, they could get a second dose of tosalizumab. And this was relative to control. Now importantly in this trial, 82% of people will also receiving corticosteroids because of the results of the original recovery trial. Their primary outcome was 28 day mortality and their statistics were the standard frequentist statistics based on an intention to treat analysis. And what they found is that there was a 4% reduction in mortality from 35% to 31% with treatment with tosalizumab. This was highly statistically significant and conferred a relative risk of 0.85. And if you look at the mortality hazard curve, you can see that the usual care group had a higher mortality that separates very early in the curve. Now in subgroup analysis in this trial, it appeared that the benefit was actually highest in the corticosteroid group because there was some concern, is tosalizumab an add-on to corticosteroids or is it an alternative to corticosteroids? And this trial, while it was a subgroup analysis, seems to suggest that it's an add-on therapy on top of corticosteroids. And we now have a large meta-analysis that looks at all the trials, including the smaller and earlier ones that didn't show a benefit at anti-IL-6 agents. What I show here is a forest plot for the tosalizumab-specific trials. And you can see that the largest trials contributing to this are the RECOVERY trial and the REMAP-CAP trial. And they seem to favor anti-IL-6 therapy with an odds ratio of 0.83. And when you specifically break down as to whether the patients received corticosteroids or not, what you can see is with any anti-IL-6 therapy, the 28-day mortality benefit favors in patients that also received corticosteroids. There's a really strong association in those patients that also received corticosteroids, but less so in patients that didn't receive corticosteroids. Now this was also true for progression to invasive mechanical ventilation for those that weren't already mechanically ventilated, ECMO, and death at 28 days. And interestingly, when you look at infections, which is the really concern of getting so much anti-inflammatory therapy is infections, they did not see an increased risk of infections in the patients that received both anti-IL-6 therapy and corticosteroid use. So that completes my part of the talk on anti-IL-6 therapies. And I want to move to another similar therapy, looking at the Janus kinase inhibitor or JAK inhibitors in severe COVID-19. I'm going to specifically focus in on biocitinib because it probably has the best evidence of the JAK kinase inhibitors. So interesting, biocitinib primarily functions as a JAK1-2 inhibitor and is FDA approved for the treatment of rheumatoid arthritis. It was first identified as a potential therapeutic for COVID-19 by an artificial intelligence platform that screens already approved drugs for potential treatments for COVID-19. Biocitinib is hypothesized to potentially impact distinct pathways that may lead to improvements in COVID-19. First, biocitinib inhibits intercellular signaling of cytokines, including IL-6, by inhibiting JAK1-2. Second, biocitinib also binds to GAK and AAK1 and inhibits AAK1, two proteins important in viral entry in pulmonary epithelial cells. Based on this information, several randomized controlled trials were conducted to evaluate the role of biocitinib in combination with other therapies in patients hospitalized with COVID-19. Biocitinib, however, has several important known risks. We know these risks from prior literature in the rheumatoid arthritis population. Those risks include severe infections, reactivation of tuberculosis, malignancy, and importantly, thrombosis. You'll see in the next few slides that these risks informed the inclusion criteria for the trials I'm going to discuss and should form the inclusion criteria for patients we select to receive biocitinib. The first major study published to show a benefit of biocitinib is the ACT-2 study. This was a double-blinded, randomized placebo-controlled trial at 67 sites, mostly in the United States, but including other countries as well. This is a follow-up study of the ACT-1 study, which was the study that showed a benefit to remdesivir. The inclusion criteria included hospitalized patients with COVID-19 that were adults, and there were a long list of exclusion criteria, but the most important ones I have listed here, which are an elevation in transaminases greater than five times the upper limit of normal, an estimated GFR of less than 30, whether the patient was neutropenic or lymphopenic, which is not uncommon in COVID, a suspicion for other infections, not SARS-CoV-2, but some other kind of viral or bacterial infection or fungal infection, and then a history of VTE, venous thromboembolism, because this drug is known to increase the risk of venous thromboembolism. Now in this trial, the intervention was baricitinib for 14 days plus remdesivir versus placebo plus remdesivir. Patients were additionally required to be on heparin prophylaxis, anticoagulation prophylaxis. Their primary outcome was time to recovery in 28 days, and they define recovery based on an ordinal scale, the WHO ordinal scale of one, two, or three. And this basically means that either had to be hospitalized, but no longer on oxygen or not hospitalized. And their secondary outcomes were mortality and clinical status at day 15, but they acknowledged that they did not power the study for mortality. And this study enrolled 1,033 patients hospitalized with COVID-19. And in the intervention group, the median time to recovery was seven days as opposed to eight days in the placebo versus plus remdesivir group with about 515 versus 518 patients enrolled in each group. Now this was statistically significant median time to recovery. And interestingly, the time to recovery was fastest or most different in patients that were most sick. So patients receiving high flow oxygen or non-invasive ventilation. If they received baricitinib, they resolved within 10 days versus 18 days in the placebo plus remdesivir group. The rate of serious adverse events was actually lower in the baricitinib plus remdesivir group than the control group at 16% versus 21%. Now when they looked at mortality, the mortality was 5.1% in the intervention group and 7.8% in the control group, which was unfortunately not statistically significant and really reflects that they enrolled a very diverse group of patients that are hospitalized with COVID-19. Now the effects also appear to be strongest among patients requiring high levels of oxygen, but not invasive mechanical ventilation. Now there are several limitations to the study. They had no statistically significant mortality benefit. It was performed prior to the results of recovery. So steroids were actually not permitted unless there was another indication and the long-term effects were not evaluated. So that brings us to the second study looking at baricitinib for the treatment of hospitalized adults with COVID-19. This is the COVE barrier study, a randomized double-blinded parallel group placebo-controlled phase three trial. So they included patients that were hospitalized with COVID-19 that had evidence of pneumonia that were adults and had elevated inflammatory markers. So specifically they had to have an elevated CRP, D-dimer, LDH, or ferritin. Now midway through the trial, they did have a protocol change based on the prior trial I just presented and patients required to be on O2 at enrollment. Now they excluded very similar groups of patients as the ACT-II trial. In addition, they excluded patients that were mechanically ventilated. Their intervention was baricitinib for 14 days plus standard of care versus placebo plus standard root of care, but importantly in this trial, different than the Act 2 trial, standard of care included dexamethasone in the majority of patients. However, high-dose steroids were prohibited unless they were needed for another indication. Their primary outcome was the proportion progressing to high-flow non-invasive ventilation, invasive mechanical ventilation, or death by 28 days. Their secondary outcome was mortality. Now they enrolled 1,525 patients between June 2020 and January 2021. Huge, massive effort, but their primary outcome was not statistically significant. So the percentage of people that progressed to high-flow non-invasive or invasive mechanical ventilation or death by day 28 was 27.8% in the intervention group versus 30.5% in the control group, and this was not statistically significant. However, to their surprise, their secondary outcome, all-cause mortality, was highly statistically significant. So it was 8% in the treatment group versus 13% in the control group, and you can see that here in this mortality curve. Now, the limitations to this study are that the primary outcome was not met. 22% of patients progressed within 24 hours, and we wouldn't really expect the baricitinib to work so quickly, so it seems like a lot of people were already on their way to meeting the outcome before even given the opportunity for baricitinib to work. They also had several protocol changes, including their enrollment criteria and their sample size midway through the trial. They don't have long-term follow-up, and there are potential long-term effects of baricitinib, and they excluded patients that were mechanically ventilated. But this does seem to suggest that baricitinib may have a mortality benefit for patients with COVID-19. Now, they did follow up this study, the same study group, by looking at patients that were on invasive mechanical ventilation or extracorporeal membrane oxygenation in an exploratory randomized controlled trial of 101 patients, 86% of whom also received corticosteroids, and they saw a really large mortality benefit. The treatment was 39% mortality versus controlled 58% mortality. This was statistically significant, although I'll remind you this is a relatively small trial, and their estimated number needed to treat was six, suggesting baricitinib can also be used in the invasively mechanically ventilated and those patients on ECMO. Now, there have been a ton of COVID studies in the last year, and I can't obviously cover all of them, and there are a lot that were really significant that I can't cover today. But namely, I think it's important to acknowledge that some of the topics I didn't cover today are COVID-19 epidemiology, and specifically how the impact of race, socioeconomic status, and ethnicity are in COVID-19. A lot of that we recognized two years ago in the very early parts of the pandemic, as well as the impact of air pollution exposure on COVID-19 risk, explaining some of the disparities in COVID-19. I also didn't cover the anticoagulation in COVID-19, which has an extensive body of literature that was developed in the last year, including prophylaxis, intermediate dose, or full anticoagulation. I didn't cover specific populations like cancer and transplant that are really showing different flavors of COVID-19. And then I didn't speak of the multisystem inflammatory syndrome that has its highest relevance in children, but is also a syndrome that is occasionally seen in adults and requires unique treatment. Hopefully, we can cover those in a future lecture. I'd like to, again, thank everybody for listening. I really appreciate your time. Hello, everyone. Welcome to the SCCM Virtual Year in Review Part 2. Thank you, Dr. Riley, for sharing your insights on COVID-19. And now I'm going to share my insights on sepsis. My name is Lakshmi Santosh, and I am an Assistant Professor of Pulmonary and Critical Care at UCSF, University of California, San Francisco. I'm also the Associate Fellowship Program Director, and you can find me on social media at LakshmiMD. I have no conflicts of interest to disclose. And my alternate title is, A Break from COVID, Back to Bread and Butter. Who knows? We'll find out, we hope. So no conflicts to disclose. Thank you to the SCCM. So when we think about, you know, how do we measure a year and the year in review in sepsis, there is just so much great literature that came out in the world of sepsis. And so this is not going to be an exhaustive journal club where we dive into the literature and each specific table. This is more going to be like a tour, a big picture overview of the year in review in sepsis, kind of the big highlights, the big papers that you should know about, and that hopefully you'll use the rest of the SCCM virtual conference to check out further, more in-detail sessions on some of these milestone papers. So we are going to take the following outline. We're going to, of course, talk about our new surviving sepsis guidelines with a big focus on what's new and what's changed. So we're not going to go through all the recommendations, but really highlight the new recommendations. We're going to talk about the different studies on the perennial question in critical care, which are the best IV fluids to use. We're going to talk a little bit about policy implications and big data, machine learning and sepsis as that's a hot topic. And we're also going to talk about what happens to our patients sort of beyond their sepsis hospitalization as intention is increasingly paid to post-intensive care syndrome or PICS. So like I mentioned, we have this landmark milestone of the new surviving sepsis guidelines with 93 new recommendations that came out in October of last year. And so we're going to give you the TLDR version, the too-long-didn't-read version, summarize things for you, but we encourage you to check out the document. So very big picture takeaways. We want to keep doing some of the great critical care evidence-based practice that we've been doing with focusing on early antibiotics, ideally within the first hour. We're going to keep using norepinephrine as our first line vasopressor of choice. We're going to keep addressing goals of care early in critical illness. The QSOFA, which was very hot a couple of years ago, is a little bit de-emphasized now. We are definitely not going to be using starches or gelatins as study after study have shown that they do not help. And hopefully the nail is finally in the coffin of vitamin C, which again, we have another study, many studies, most recently the AXE trial showing that it does not help. We're going to start talking about balanced crystalloids, and we'll dive more about that in our section on IV fluids. We're also going to keep doing high-flow nasal cannula and sepsis with hypoxemic respiratory failure. High flow is preferred to non-invasive. And then the recent trials, adrenals, approaches, et cetera, talking about the use of steroids in refractory shock when you're on multiple vasopressors. So let's dive into some of these high-level recommendations in a little bit more detail. So the surviving sepsis guidelines and the campaign thought some of these recs are just very critically important and warrant their own infographic poster to disseminate widely within your hospital. So they need two. The first one is about antibiotics timing. And they say, whether shock is present or absent, if you think sepsis is definitely happening or probably happening, we need to administer antimicrobials immediately, ideally within the first hour to get that early mortality benefit. And that even if it's possible, if it's quite high on your diagnosis, thinking about administering these antibiotics immediately. Again, if you're in shock, it's easy. Just give those early antibiotics, broad-spectrum antibiotics. And even if shock is not present, you need to think about early antibiotic therapy. But also, if shock is not present, rapidly reassessing to see, could this be a sepsis mimic? Could this be non-infectious contributors to sepsis? And then you have a little bit more time if the patient is not in shock to kind of distinguish, am I in sepsis or a sepsis mimic? And they talk about doing a history, of course, physical exam, relevant labs, further data gathering to make that definitive assessment. Is this sepsis that I'm dealing with, or is this a sepsis mimic or a non-infectious cause? The second big kind of infographic that they put up that they wanted to emphasize was about vasopressors. And again, we're reaffirming and strongly recommending Norapy as the first-line vasopressor, targeting a map of 65. And some recommendations that were more recommended, not as strongly, were things like considering an A-line for arterial monitoring of pressures. A new recommendation saying that peripheral vasopressors should be strongly considered, should be considered if you are unable to have central access just yet. And they note in the asterisks here, especially make sure, all usual precautions, that this is a large bore, well-situated, closely serially monitored IV that you're doing peripheral vasopressors in, that you have metrics after which you are going to need to switch to central access, this is a temporary thing, this is not indefinite, et cetera. And that if the map is uncontrolled despite norepinephrine, we're going to add vaso. And that if we think that there's concurrent cardiac dysfunction, or if there's persistent shock despite volume resuscitation, thinking about whether we need to add either some inotropic support with dobutamine or switching to epinephrine. So these are kind of our tried and true recommendations, just re-emphasizing these with very few tweaks from the recommendations that we've followed in the past. And so who specifically kind of got upgraded or downgraded that they really note? So they have a nice table in the surviving sepsis guidelines that actually talk about explicitly who got upgraded and who got downgraded. And so one big downgrade was the infamous 30 cc's per kg fluid resuscitation recommendation. And especially since that was tied often to incentive payments and performance metrics, many frontline providers, clinicians in the emergency room and urgent care and critical care felt like this blanket recommendation of 30 cc's per kg was not always appropriate, not always appropriate for people who had heart failure, kidney failure, liver failure, etc. And so this is less of a strong recommendation that's now been downgraded. Who got upgraded? So the recommendations for using steroids in refractory shock, and specifically they call out a dose of IV hydrocortisone 200 if you're in persistent shock despite multiple vasopressors. And then of course the recommendation again for crystalloids being significantly stronger than colloid, gelatins, starches, that was also called out specifically as well. So this is kind of a quick summary of who got upgraded and who got downgraded in the latest guidelines. So switching gears, because we've already been talking about fluids, the perennial question comes up of which fluids? And we had a bunch more trials that, you know, it didn't clarify things completely. And so there's more for us to study. So the first trial that we're going to talk about is the BASICS trial, of course. And I'm going to use this format for my slides where kind of the PICO format where we're going to talk about our population, what was the intervention, what was the control group, and what was the outcome study. So the BASICS trial looked at 75 Brazilian ICUs patients in there, and they did a two-by-two well-designed trial. It was an RCT of balanced solution like plasmolyte versus normal saline. And they also looked at slow versus fast infusion rates. So they were looking at again plasmolyte or balanced crystalloid solution versus normal saline. And their primary outcome was 90-day survival, 90-day mortality. And they found no difference actually between saline and plasmolyte. And when they did look at the second part of that analysis of the rate of infusion, which addresses the question of, you know, how quickly should we resuscitate? And they looked at, you know, again, these 10,500-plus patients, randomizing them to 333, which was slow, and 999, which was fast, 999. And they found that, you know, again, no significant difference, which should be somewhat more reassuring that if you need to bolus wide open at 999, you know, there's not harm there. So I think that arm was actually more reassuring, provided reassurance to practice that once you need, once you think someone is fluid responsive, you need to give them a bolus wide open, there's no harm for giving it acutely at that fast infusion rate of 999. And so the next study that came out soon after was the PLUS study. And the PLUS study looked at 5,037 patients in 53 ICUs in Australia and New Zealand, again, looking at plasmolyte versus normal saline and 90-day mortality. And this was a trial that affirmed the BASICS trial in that there were no significant mortality differences and no significant renal outcome differences. You see here the Kaplan-Meier curve with almost complete overlap between the saline group and the P-like group, you know, overlapping curves. And you see the maximum creatinine, increase in creatinine, receipt of renal replacement therapy, also not significantly different either. I think the big kind of critique of this trial that people have discussed is that the majority of the plasmolyte group, as is done in most institutions, are receiving a lot of medications that are still running in normal saline. Again, if you have septic critically ill patients, they're getting a lot of medications like antibiotics and other continuous infusions that are usually prepared in normal saline. So the question was, did this perhaps attenuate the benefit scene of the plasmolyte group? And so, you know, we have prior literature, you know, the SMART trial and others, which had shown us that the preference for balanced crystallide solutions like plasmolyte, and then these two trials, PLOS and BASICS, raising the question of, does it really matter? Are we back to that therapeutic nihilism and critical care? It actually doesn't matter. Volume is volume, as long as you're using a crystalloid. And so I think further studies and meta-analyses are on the way to really decide this. I think for now, at our institution, the practice is still to favor, you know, based on the earlier trials, to favor plasmolyte as a balanced crystalloid solution. And that, you know, time will tell about how these benefits hold up or if it does matter or not. But I think that this argument of whether this benefit was attenuated is an important one. And we do have prior literature with the SMART trial and others showing the benefits of balanced crystalloids. So I'm not changing my practice quite yet to abandon balanced crystalloids, but we'll see. We're watching that data closely. And the other thing to know is that fluids are, of course, just one component of our resuscitation. I like this graphic from Jenser and colleagues in CHESS, where they talked about, you know, early shock, severe shock, refractory shock, that we have a bunch of tools in our toolbox, right? And fluid resuscitation is just one of those many tools that we're using. In addition to vasopressors, of course, we're thinking about the whole path of physiology and identifying and treating hypovolemia with fluids. But also we're treating most of these patients of severe acidemia. Many of them are on continuous renal replacement therapy. If they're hypocalcemic, we're giving them calcium. We're thinking about how to combine our vasopressors. You know, do we need to add vaso or epinephrine? We're thinking about our adjunctive agents, as mentioned, like hydrocortisone. We're thinking about do they need rescue therapies like methylene blue, things like that. And so, you know, fluids are just one tool in our toolbox that we have to remember. So don't get too nihilistic. And, you know, another graphic from the same article just showing us that we have to think about what people's cardiac output is and their fluid responsiveness and really assess those in a two-by-two session. What is the cardiac output? What is the fluid responsiveness? To think about, of course, just like we teach our med students on the first day, you know, what type of shock are we in and how do we best treat that? And so that's just a quick couple of moments thinking about our perennial question of which fluid. And so the jury is still out. Next, moving on to this concept of big data and sepsis. There was a lot of trials and controversy about the role of big data and machines, man versus machine, when it came to sepsis. And so this is a graph from my institution that is often heralded as that, you know, our sepsis mortality once we started the electronic sepsis surveillance, we use EPIC as our EHR in the emergency room and on the inpatient units, you know, our adult sepsis mortality actually dropped. And so this is a graph that we see in a lot of our QI meetings, etc., showing about the benefits of electronic sepsis surveillance with tools like our EHR EPIC. And at the same time, we recognize the limitations, right? We have to resist that lactobolus reflex and always click reorder whenever we get a call from the bedside nurse saying the lactate is slightly elevated. And so how do we kind of reconcile these? And this has been in the news a lot recently. You know, there is this stat news investigation with EPIC saying that the algorithms for which they're detecting sepsis are under a corporate firewall and they're not necessarily accurate. And there was another article that came out just a few weeks ago talking about how subtle shifts in patient data over time can actually significantly change the outcome, which undermines patient safety. And so in the literature, the big trial that came out that made these news waves was this trial in JAMA Internal Medicine by Wong and colleagues, which actually looked at a very robust data set of 38,000 hospitalizations at Michigan and found that the prevalence of sepsis in these patients doing chart review was about 7%. And EPIC missed 67% of those cases. And there were though sepsis alerts, the familiar sepsis alerts triggered for 7,000 patients about, but the positive predictive value was only about 12%. So low positive predictive value, lots of false positives. And that I think drives experientially what many of us see is that we just click through the sepsis alert because they're firing kind of indiscriminately, you know, on 7,000 patients when it's actually only 2,500 patients. And so that tracks with my experience at least. And there's been a number of trials that have come out since then. A lot of them from Dr. Prescott's group, Dr. Haley Prescott's group, you know, this one looked at what are the encounters that people have with the healthcare system in the week before sepsis? I really like this paper because they basically talk about how most patients who come in later with sepsis or septic shock have seen a healthcare provider, whether it's ER, urgent care, outpatient clinic, you know, primary care in the preceding week. So we have a lot of opportunities actually to catch that sepsis and intervene early. Nice paper. This is another paper from colleagues at Washington University in St. Louis looking at sepsis prediction tools using AI machine learning for the general ward setting. So how do we kind of detect this, predict this before these patients even hit our ICUs? And another paper from Dr. Prescott's group and annals of ATS looking at, you know, different methods to define baseline organ function when you're looking at sepsis. So, you know, even though there were these terrible headlines about Epic and EHR algorithms, you know, not being sensitive enough, there's a lot of great research from fantastic investigators, critical care investigators, who are really trying to change this and make things more precise and actually try to detect sepsis in patients before they clinically present. So it's an exciting area to watch, I think, in the years ahead. And lastly, to round out our year in review, thinking about the ongoing literature about what happens for our patients beyond sepsis. And, you know, as we know, there's about 1.4 million sepsis survivors every year. And these patients are not, quote, back to normal. They're left not only with physical challenges, but also mental health challenges, cognitive challenges, emotional challenges. And I think there's more awareness of this now, perhaps with COVID and long COVID. But for our bread and butter, you know, poor critical care patient population, this has been a huge issue for decades. And, you know, I like this graphic from Nature and it reviews nephrology showing how there's this early mortality, of course, in sepsis from systemic inflammation. But there's also this delayed mortality and long-term mortality related to, you know, long-lasting immune dysregulation, perhaps increasing susceptibility to things like cardiovascular disease and cancer. And again, this is also being aggressively studied and researched during COVID. But we know that even our sepsis survivors not from COVID are experiencing, you know, long-term sequelae as well. And so, you know, in COVID, we know well that this great figure from Nalbandani and colleagues in Nature about the chronic symptoms that happen post-acute illness, post-critical illness, and in many cases, even without being hospitalized, everything from general symptoms to pulmonary symptoms, neurological, cardiac, you know, increased susceptibility to blood clots, renal injury. And that's why I think you've seen this last pandemic year or two, a proliferation of not just post-ICU clinics and post-COVID clinics, but more centers that are linking them explicitly together. Because I think what we found that our PICS framework, which actually looks systematically at mental health, pulmonary health, cognitive health, and physical health, and focus on family caregiver health is very translatable from PICS to COVID. And so, this study with the Cairo group of post-critical illness clinics run by Dr. Dinesh and colleagues looked at, you know, all these new clinics that have sprung up with post-ICU and post-COVID clinics really around the U.S. And they found, you know, again, if you've anecdotally been hearing about a lot more clinics popping up recently, that's true. And I think that's because you see here this huge number of ICU recovery clinics that started in 2020. And I think many institutions like ours at UCSF, they wanted to do a PICS clinic for many years, but there was a lot of barriers. And then when COVID hit, you know, navigating those barriers creatively to create these longitudinal and sustainable ICU recovery clinics was very helpful. And so, I hope that in this half hour, we talked about, you know, the new surviving sepsis guidelines, took a whirlwind tour, talked about the new literature about sepsis and septic shock fluid management. We talked about big data in sepsis and what did the latest tool show us, and a little bit about what happens beyond sepsis and how do we take care of patients when they're surviving critical illness and septic shock. And so, if you thought your favorite article wasn't quite here, addressed by me nor Dr. Riley, you know, again, it's too bad we couldn't meet in Puerto Rico, but we'd love to hear from you. Feel free to email me or find me on social media. Thank you so much for listening, and thank you for your time. Enjoy the rest of the virtual conference.

COVID-19 critical illness

new therapies

steroids

anti-interleukin-6 therapies

Janus kinase inhibitors

supportive care

remdesivir

recovery study

post-ICU care